Novel Approaches to the Management of Myeloma

Standard therapy for multiple myeloma, which accounts for 10% of all hematologic malignancies, has been autologous stem cell transplantation (ASCT), alkylator-based chemotherapy, and corticosteroids. Several advances have been made in the treatment of multiple myeloma over the past decade, especially the arrival of new, active agents such as thalidomide (Thalomid), bortezomib (Velcade), and lenalidomide (Revlimid). These have shown significant clinical activity as single agents. Trials are ongoing to incorporate these new agents into the various stages of treatment and to combine them with other effective treatment modalities, including ASCT.

Multiple myeloma accounts for 10% of all hematologic malignancies.[1,2] For many years, autologous stem cell transplantation (ASCT), alkylatorbased chemotherapy, and corticosteroids had been the mainstay of therapy for the disease. Recently, thalidomide (Thalomid), bortezomib (Velcade), and lenalidomide (Revlimid) have emerged as effective single agents, demonstrating significant clinical activity in relapsed and refractory myeloma.[ 3-5] The discovery of these drugs has been accompanied by a growing awareness of the importance of bone marrow microenvironmental changes such as induction of angiogenesis, suppression of cell-mediated immunity, and expression of various adhesion molecules and cytokines in disease progression.[6,7] The present challenge is to determine how best to incorporate thalidomide, bortezomib, and lenalidomide into the therapeutic strategy for myeloma. This article will briefly summarize the efficacy data in myeloma with these three drugs, and discuss how they are being incorporated into standard clinical practice and clinical trials for the treatment of this disease. Thalidomide and Lenalidomide Thalidomide was first tested in myeloma based on the known antiangiogenic properties of the drug coupled with the knowledge that increased angiogenesis occurred in myeloma similar to solid tumors.[8,9] The first trial in the disease was conducted at the University of Arkansas and demonstrated a response rate of 25% in heavily pretreated patients with relapsed and refractory disease.[3] Since then several studies have confirmed the activity of thalidomide in relapsed myeloma, with a response rate of approximately 25% to 35% and a median response duration of 1 year.[10-13] Thalidomide has been effectively combined with dexamethasone (Thal- Dex) in the treatment of both newly diagnosed and relapsed myeloma. Response rates with Thal-Dex are approximately 65% to 70% in newly diagnosed disease and 50% in the relapsed, refractory setting.[14-20] Recent studies suggest that efficacy can be further increased with the addition of alkylating agents.[12,21,22] The usual thalidomide dose is 50 to 200 mg/d. The main disadvantage with this drug is nonhematologic toxicity, such as constipation, sedation, neuropathy, rash, and teratogenicity. Safer and more potent analogs of thalidomide are being developed; lenalidomide is one of the first analogs to enter clinical trials. Lenalidomide has shown promis-ing antimyeloma activity in two phase I trials.[5,23] In a subsequent phase II trial of 83 evaluable patients with relapsed myeloma, 24% responded to therapy. This trial included several patients who had previously failed thalidomide. Two large phase III trials in relapsed myeloma comparing lenalidomide plus dexamethasone vs dexamethasone alone have been completed. An independent data monitoring committee has recommended closure of these trials because of significantly superior time to progression with lenalidomide plus dexamethasone compared to dexamethasone alone. Detailed results are expected later this year.

Typical dosing for myeloma is 25 to 30 mg/d on days 1 through 21 of a 28-day cycle. The most common adverse effects are thrombocytopenia and neutropenia. Side effects such as sedation, constipation, and neuropathy appear to be uncommon with lenalidomide. Bortezomib Bortezomib is a boronic acid dipeptide, and the first proteasome inhibitor to enter clinical trials.[24,25] Normally, cellular proteins targeted for destruction are first tagged by the addition of ubiquitin molecules. Ubiquitinated proteins are then identified and degraded in the proteasome complex. Bortezomib is a specific inhibitor of the proteasome complex, and the resultant inhibition of this catabolic pathway leads to cell-cycle arrest and apoptosis. Based on promising preclinical and phase I data, a large phase II study of bortezomib was undertaken in relapsed and refractory myeloma. Of 193 evaluable patients, 27% achieved a significant response to therapy. In another trial, which tested two different dosing schedules, responses were seen in 33% and 50% of patients at the 1.0 mg/m² (28 patients) and 1.3 mg/m² (26 patients) dosing levels, respectively.[ 26] Preliminary results from a large randomized trial indicate superior time to progression and overall survival with bortezomib compared to dexamethasone in relapsed, refractory myeloma.[27] The starting dose is 1.3 mg/m² given on days 1, 4, 8, and 11 every 21 days. The most common side effects are gastrointestinal, cytopenias, fatigue, and peripheral neuropathy. Incorporation of New Agents Into the Treatment of Myeloma The treatment of myeloma usually consists of various phases, such as induction, consolidation-typically with ASCT-maintenance, and treatment of relapsed and refractory disease. Clinical trials incorporating these new agents have been designed to address each phase of therapy. Further, trials are ongoing in specific subsets of patients, including those felt not to be transplant candidates because of advanced age or poor performance status, and those felt to have high-risk myeloma. Studies are also ongoing in patients with smoldering myeloma in an attempt to delay progression to symptomatic disease. Newly Diagnosed Myeloma Patients with newly diagnosed myeloma are treated based on whether they are candidates for ASCT, because two published randomized trials have shown that ASCT prolongs survival in myeloma.[28,29] Patients who are candidates for ASCT need to avoid alkylator-based induction to prevent stem cell damage. Four cycles of vincristine, doxorubicin (Adriamycin), and dexamethasone (VAD) had been the typical induction regimen used in this population of patients. But VAD had significant disadvantages, including the need for an indwelling intra-venous line, neurotoxicity from vincristine, cardiotoxicity from doxorubicin, and alopecia. Furthermore, vincristine and doxorubicin have negligible antimyeloma activity as single agents, and most of the efficacy of VAD is derived from dexamethasone alone. These facts, coupled with the significant activity of oral Thal-Dex in newly diagnosed myeloma, have negated the need for VAD as induction therapy. Preliminary results of a randomized trial show superior response rates with Thal-Dex compared to dexamethasone alone. But Thal-Dex is complicated by a higher incidence of grade 3/4 adverse effects than dexamethasone alone. This is especially true of deep-vein thrombosis, for which prophylaxis should be considered in all patients started on Thal- Dex. So how do we decide on the best induction therapy in standard practice outside a clinical trial setting? The main standard and clinical trial options for patients with various subcategories of newly diagnosed myeloma are summarized in Table 1. After considering the risks and benefits for patients proceeding to early transplant, dexamethasone alone may be adequate pretransplant induction if a delay of 1 to 2 months to assess response can be safely incurred, with the plan of adding thalidomide if response is inadequate. Thal-Dex can be reserved for those patients with more aggressive disease such as painful symptoms, large lytic lesions, impending cord compression, hypercalcemia, or renal failure. On the other hand, dexamethasone alone may not be adequate if an early transplant is not planned. Several ongoing trials are seeking to improve upon results with dexamethasone and Thal-Dex for these patients. Lenalidomide plus dexamethasone (Rev-Dex) is being tested in large randomized trials by the Eastern Cooperative Oncology Group (ECOG) and the Southwest Oncology Group (SWOG) in an attempt to improve efficacy and reduce toxicity. Preliminary results from a phase II Mayo Clinic trial indicate response rates greater than 80% with Rev-Dex in newly diagnosed myeloma, with fewer toxicities than previously observed with Thal-Dex.[30] This strategy is particularly appealing to patients who are proceeding to an early transplant and wish a safe and convenient oral induction regimen. Bortezomib alone appears to be active in newly diagnosed myeloma.[ 31,32] The addition of bortezomib to Thal-Dex seems to greatly improve overall and complete response rates,[33] and will appeal to patients and physicians who seek alternatives to transplant as initial therapy, relegating ASCT to a salvage role. All of these strategies are currently in the clinical trial stage and patients should be encouraged to participate in these trials as much as possible in preference to off-study therapy. For the subset of patients not considered to be transplant candidates because of advanced age or poor performance status, advances have been harder to come by. Melphalan (Alkeran) and prednisone (MP) has remained the standard initial treatment for this group for over 3 decades. Ongoing trials are seeking to improve upon this by adding new agents to the classic MP regimen. The addition of thalidomide to MP increased response rates and prolonged progression-free survival in two recent trials; however, no improvement has been seen yet in overall survival.[34,35] Studies are also ongoing with the addition of bortezomib (the MPV regimen) and lenalidomide (the MPR regimen) to MP. Improving the outcome of this group of patients is critically needed, and identifying effective ways of incorporating new agents into the initial treatment strategy is necessary to achieve this goal. Consolidation/Stem Cell Transplantation One of the main questions raised by patients today is whether the arrival of new drugs signals the end of upfront ASCT in the treatment of myeloma. Clearly, well-designed studies are needed to answer this question, and until then ASCT should still be considered in all eligible patients. Autologous stem cell transplantation can, however, be delayed and performed as salvage therapy at the time of relapse in selected patients, provided stem cells are harvested and cryopreserved early in the disease course. At least three randomized trials show that this approach is equivalent to early stem cell transplant.[ 36-38] However, at the Mayo Clinic we still feel it is preferable to proceed with up-front ASCT in eligible patients because it affords the opportunity to consider tandem ASCT, reduces issues related to advancing age and comorbidity, and avoids insurance approval issues. Clinical trials are ongoing to test the addition of new agents to improve the effectiveness of ASCT. For example, the addition of bortezomib to melphalan as the condition regimen is now being tested as a way of improving outcome following ASCT.[39] Alternatively, the ECOG is developing a phase II clinical trial to test a novel nontransplant consolidation strategy following induction therapy. Maintenance Therapy There have been several trials testing various maintenance strategies in myeloma for patients completing chemotherapy or ASCT. Most have been disappointing. Prednisone at 50 mg every other day has shown some benefit in steroid-responsive patients treated without ASCT.[40] Recently thalidomide was shown to prolong progression free survival but not overall survival following ASCT.[41] More data are needed. It would be preferable for patients to enroll in ongoing studies that are testing thalidomide (National Cancer Institute of Canada trial, Clinical Trials Network trial) or lenalidomide (Cancer and Acute Leukemia Group B trial) as maintenance therapy. Treatment of High-Risk Myeloma Patients with deletion 13 or hypodiploidy by karyotype, plasma cell labeling index > 3%, or translocations t(4;14), or t(14;16) have highrisk myeloma and tend to do poorly even with tandem ASCT. These patients should be considered for novel therapeutic strategies. Clinical trials need to be designed separately for these patients; one such trial with bortezomib as initial therapy is currently ongoing in the ECOG. Relapsed Disease All new agents discussed in this article were first identified because of their single-agent activity in relapsed and refractory myeloma. Numerous studies are currently ongoing to develop novel combination approaches. The most well-studied combinations are Thal-Dex and bortezomib plus dexamethasone. The aggressiveness of the relapse and the performance status of the patient often dictate the choice of single- agent vs combination approaches in the relapsed setting. Summary Several advances have been made in the treatment of multiple myeloma over the past decade, especially the arrival of new, active agents. Trials are ongoing to incorporate these new agents into the various stages of treatment and to combine them with other effective treatment modalities, including ASCT. However, more active new drugs are still needed.

Disclosures:

Dr. Rajkumar has received financial support for clinical trials at the Mayo Clinic from Celgene, Millennium, and Entremed.

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